CN109406706A - Method of the nicorandil tablet in relation to substance is measured using HPLC corrector factor method - Google Patents
Method of the nicorandil tablet in relation to substance is measured using HPLC corrector factor method Download PDFInfo
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- CN109406706A CN109406706A CN201811446229.2A CN201811446229A CN109406706A CN 109406706 A CN109406706 A CN 109406706A CN 201811446229 A CN201811446229 A CN 201811446229A CN 109406706 A CN109406706 A CN 109406706A
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- nicorandil
- solution
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- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 title claims abstract description 157
- 229960002497 nicorandil Drugs 0.000 title claims abstract description 154
- 238000000034 method Methods 0.000 title claims abstract description 66
- 239000000126 substance Substances 0.000 title claims abstract description 27
- 238000004128 high performance liquid chromatography Methods 0.000 title claims abstract description 17
- 239000012535 impurity Substances 0.000 claims abstract description 189
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000007788 liquid Substances 0.000 claims abstract description 27
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 claims abstract description 25
- 238000001514 detection method Methods 0.000 claims abstract description 13
- -1 trifluoroacetic acid-triethylamine-tetrahydrofuran-water Chemical compound 0.000 claims abstract description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 72
- 239000000243 solution Substances 0.000 claims description 58
- 238000012360 testing method Methods 0.000 claims description 40
- 239000013558 reference substance Substances 0.000 claims description 37
- 238000010790 dilution Methods 0.000 claims description 26
- 239000012895 dilution Substances 0.000 claims description 26
- 239000012085 test solution Substances 0.000 claims description 23
- 230000014759 maintenance of location Effects 0.000 claims description 22
- 239000011550 stock solution Substances 0.000 claims description 22
- 238000012937 correction Methods 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 239000011734 sodium Substances 0.000 claims description 14
- 229910052708 sodium Inorganic materials 0.000 claims description 14
- 229920002472 Starch Polymers 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 12
- 235000019698 starch Nutrition 0.000 claims description 12
- 239000008107 starch Substances 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 238000010828 elution Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 239000003643 water by type Substances 0.000 claims description 5
- 238000004364 calculation method Methods 0.000 claims description 4
- 238000010812 external standard method Methods 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000012417 linear regression Methods 0.000 claims description 4
- 229940031651 nicorandil 20 mg Drugs 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 238000005259 measurement Methods 0.000 abstract description 10
- 239000012071 phase Substances 0.000 description 40
- 239000000523 sample Substances 0.000 description 14
- 239000003814 drug Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 206010002383 Angina Pectoris Diseases 0.000 description 9
- 230000017531 blood circulation Effects 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 210000002216 heart Anatomy 0.000 description 9
- 230000000295 complement effect Effects 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 210000004351 coronary vessel Anatomy 0.000 description 6
- 230000002107 myocardial effect Effects 0.000 description 6
- 102000016924 KATP Channels Human genes 0.000 description 5
- 108010053914 KATP Channels Proteins 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000003834 intracellular effect Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 229910002651 NO3 Inorganic materials 0.000 description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 230000024883 vasodilation Effects 0.000 description 4
- 206010003225 Arteriospasm coronary Diseases 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 208000003890 Coronary Vasospasm Diseases 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 210000004413 cardiac myocyte Anatomy 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 201000011634 coronary artery vasospasm Diseases 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 229960003966 nicotinamide Drugs 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 230000036284 oxygen consumption Effects 0.000 description 3
- 239000004036 potassium channel stimulating agent Substances 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 102000004506 Blood Proteins Human genes 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000004004 anti-anginal agent Substances 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- NJJZHNHMKRHNOL-WEVVVXLNSA-N chembl3209798 Chemical compound C1C2=NON=C2C(=N/O)/CC21OCCO2 NJJZHNHMKRHNOL-WEVVVXLNSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 239000003218 coronary vasodilator agent Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002530 ischemic preconditioning effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 230000000116 mitigating effect Effects 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 235000005152 nicotinamide Nutrition 0.000 description 2
- 238000011017 operating method Methods 0.000 description 2
- 230000000661 pacemaking effect Effects 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- DVSPHWCZXKPJEQ-UHFFFAOYSA-N 2-methoxyethyl(trimethyl)azanium Chemical compound COCC[N+](C)(C)C DVSPHWCZXKPJEQ-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- WUWYBBGJBJWBJK-UHFFFAOYSA-N C1CCOC1.CCN(CC)CC.OC(=O)C(F)(F)F Chemical compound C1CCOC1.CCN(CC)CC.OC(=O)C(F)(F)F WUWYBBGJBJWBJK-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- UFHFLCQGNIYNRP-VVKOMZTBSA-N Dideuterium Chemical compound [2H][2H] UFHFLCQGNIYNRP-VVKOMZTBSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003257 anti-anginal effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
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- 230000009460 calcium influx Effects 0.000 description 1
- 230000008061 calcium-channel-blocking effect Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000005961 cardioprotection Effects 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013928 guanylic acid Nutrition 0.000 description 1
- 239000004226 guanylic acid Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002102 hyperpolarization Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000010220 ion permeability Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 244000309715 mini pig Species 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 150000005480 nicotinamides Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000003450 potassium channel blocker Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 230000033904 relaxation of vascular smooth muscle Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to use HPLC corrector factor method to measure method of the nicorandil tablet in relation to substance.This method is measured according to the specification in the contained high performance liquid chromatography of Chinese Pharmacopoeia four general rules 0512 of version in 2015, with C18 chromatographic column, it is mobile phase measurement with trifluoroacetic acid-triethylamine-tetrahydrofuran-water mixed liquid, the impurity for capableing of Simultaneous Determination includes impurity A, impurity B, impurity C, impurity D, impurity E and related unknown impuritie, and there is excellent methodology performance, such as the detection range of linearity is wide, linearly good, detection limit and quantitative limit are small, precision is good.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to the method for quality control of drug, more particularly to nicorandil tablet
Related substance detecting method, more particularly to using the related substance of HPLC corrector factor method measurement nicorandil tablet
Method.The method of the present invention can be reliably simultaneously to such as impurity A, impurity B, miscellaneous of many related substances in nicorandil tablet
Matter C, impurity D, impurity E carry out quantitative detection, and have excellent methodology performance.
Background technique
Nicorandil (Nicorandil), entitled N- (2- the ethoxy)-niacinamide nitric acid rouge of chemistry, N- [2-
(Nitrooxy) ethyl] -3-pyridinecarboxamide, molecular formula C8H9N3O4, molecular weight 211.17, chemical structure
Formula are as follows:
Nicorandil category nitrate compound is a kind of ATP sensitive Potassium Channel Opener, is clinically mainly used for being preced with
Heart trouble, anginal treatment (Nicotinamide derivative；exhibits dual mechanism of action
as both nitrovasodilator and potassium channel activator.Prepn:H.Nagano et
al.,DE 2714713(1977,Chugai)；Yasumi Uchida,M.D.,Nobuo Yoshinoto,et al.Effect
of 2-Nicotinamidethyl Nitrate(SG 75)on Coronary Circulation,Jap.Heart J.,
1978,19,112-124；Wear poetic prose, Xu Jingfeng antianginal new drug-Nicorandil, new drug and clinical, 1985,4 (4), 34-35；
Effect of Xu Min, Jiang Lili the nicorandil in disease treatment, Chinese Journal of New Drugs, 1999,8 (9), 590-592).It is domestic
Nicorandil tablet current standard is national standard WS-10001- (HD-0151) -2002 (Chinese Pharmacopoeia Commission's national drug standards
Drug provincial standard rising second Beijing of national standard: China Medical Science Press, 2002,61), uncharged related
Substance check item, and its content assaying method is ultraviolet E value method, specificity is poor, causes the country for a long time to nicorandil tablet
Related substance situation awareness does not go deep into.Though British Pharmacopoeia has the nicorandil tablet Related substances separation recorded using HPLC method at present
, and method is changed in version within 2017 at it, but its new and old two method (TheBritish
Pharmacopoeia Commission Office.BP2016.London:The stationery on behalf of
MHRA,2016,905-907；The British Pharmacopoeia Commission Office.BP2017.London:
The stationery on behalf of MHRA, 2017,937-939) it can not efficiently separate the domestic nicorandil of analysis
The related substance of piece, especially such as be mentioned above impurity A, impurity B, impurity C, impurity D, in terms of typical process impurity E
Impurity, and be of great significance to efficiently separating for these impurity for the quality control of domestic nicorandil tablet, such as it is right
Related substance in domestic nicorandil tablet is effectively separated analysis, and is used for imitation medicine Conformance Assessment, this is for state
The quality conformance analysis of interior imitation medicine is of great significance.
Therefore, this field still expects to have new method to be effectively separated point to the related substance in nicorandil tablet
Analysis, especially such as the impurity A being mentioned above, impurity B, impurity C, impurity D, effectively analyzed impurity E.
Summary of the invention
The purpose of the present invention is to provide a kind of new methods, for having to the related substance in nicorandil tablet
Effect separation analysis, especially such as others are for example mentioned above impurity As, impurity B, impurity C, impurity D, impurity E into
The effective analysis of row.It has been unexpectedly discovered that can be effectively in domestic nicorandil tablet using the method for the present invention
Related substance especially carried out such as the impurity A, impurity B, impurity C, impurity D, exemplary impurity impurity E being mentioned above it is effective
Separation analysis is accomplished the present invention is based on this discovery.
For this purpose, first aspect present invention provide it is a kind of using high performance liquid chromatography to related in nicorandil tablet
The method that substance is detected comprising following operation:
(1) it is surveyed according to the specification in the contained high performance liquid chromatography of Chinese Pharmacopoeia four general rules 0512 of version in 2015
It is fixed；
(2) chromatographic condition and system suitability: with the chromatographic column (example that octadecylsilane chemically bonded silica is filler
Such as, the specification of chromatographic column be 150~300mm (such as 250mm) × 4.6mm, 5 μm), with trifluoroacetic acid-triethylamine-tetrahydro furan
Mutter-water (3:5:3:989) be mobile phase A, with water: tetrahydrofuran: triethylamine: trifluoroacetic acid (972:20:5:3) be Mobile phase B,
Gradient elution program shown according to the form below carries out gradient elution, flow velocity 1.2ml/min, and column temperature is 25 DEG C, and Detection wavelength is
262nm,
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0.0 | 100 | 0 |
| 22 | 100 | 0 |
| 54 | 0 | 100 |
| 65 | 0 | 100 |
| 66 | 100 | 0 |
| 75 | 100 | 0 |
In system suitability solution chromatogram, the retention time of nicorandil is (such as 34 within the scope of 33~40min
~38min), number of theoretical plate should be not less than 5000 based on nicorandil peak, the separating degree between nicorandil and other impurities peak
It should be greater than 3；
(3) prepared by solution:
The fine powder for taking the nicorandil tablet for being equivalent to nicorandil 20mg to be ground into, it is accurately weighed, it sets in 10ml measuring bottle, uses
Dilution shaking dissolves and is diluted to scale, shakes up, and filters, takes test solution of the subsequent filtrate as Related substances separation
(its concentration is equivalent to 2000 μ g/ml)；
Nicorandil reference substance 20mg is taken, it is accurately weighed, it sets in 10ml measuring bottle, is dissolved with above-mentioned dilution and be diluted to quarter
Degree, shakes up, the reference substance stock solution that concentration is equivalent to 2000 μ g/ml is made；Precision measures reference substance stock solution 1ml, sets 100ml
It in measuring bottle, with above-mentioned diluted to scale, shakes up, as reference substance solution (its concentration is equivalent to 20 μ g/ml)；
Dirt solution: precision weighs each impurity 10mg, is set in 10ml measuring bottle respectively, is dissolved and is diluted to above-mentioned dilution
Scale shakes up, and the stock solution that each impurity concentration is equivalent to 1000 μ g/ml is respectively prepared；It is accurate respectively to measure each impurity stock solution
1ml is set in 100ml measuring bottle, with diluted to scale, is shaken up, and as each dirt solution, (its concentration is equivalent to 10 μ g/
ml)；
System suitability solution: taking nicorandil reference substance 20mg, accurately weighed, sets in 10ml measuring bottle, in addition to
Accurate each impurity stock solution 0.1ml of addition is shaken up with diluted to scale respectively in the measuring bottle, as system suitability
Testing liquid (its concentration is equivalent to 2000 μ g/ml of nicorandil, 10 μ g/ml of each impurity)；
(4) it measures:
Precision measures 10 μ l of reference substance solution, injects liquid chromatograph, records chromatogram, reads nicorandil in chromatogram
Retention time, peak area；
Precision measures each 10 μ l of dirt solution, is injected separately into liquid chromatograph, records chromatogram, reads each in chromatogram
The retention time of a impurity, peak area, and determine the retention time of each impurity；
Precision measures 10 μ l of system suitability solution, injects liquid chromatograph, records chromatogram, reads in chromatogram
The retention time of each chromatographic peak, peak area calculate between the number of theoretical plate, nicorandil and other impurities peak at nicorandil peak
Separating degree, calculate each impurity phase for the relative retention time of nicorandil；
Precision measures 10 μ l of test solution, injects liquid chromatograph, records chromatogram, reads nicorandil in chromatogram
And the area of each impurity；If any known impurities peak in test solution chromatogram, with nicorandil peak area in reference substance solution
For control, the content of the impurity in tablets is calculated by external standard method multiplied by after its correction factor with the impurity peak area.
According to method of the first aspect of the present invention, wherein the impurity is selected from impurity A, impurity B, impurity C, impurity D, impurity
E。
According to method of the first aspect of the present invention, the wherein chemical structure of impurity A, impurity B, impurity C, impurity D, impurity E
Formula difference is as follows:
According to method of the first aspect of the present invention, wherein further including the mistake for measuring and calculating the correction factor of each impurity
Journey, specifically: using the stock solution of reference substance stock solution and each impurity, with diluted in 2 μ of μ g/ml~50 g/ml
7 concentration point test fluids in concentration range, measure under 262nm wavelength, respectively to nicorandil and each impurity with concentration pair
Peak area carries out linear regression, with the correction of nicorandil linear gradient and the ratio calculation impurity of each impurity linear gradient because
Son.
According to method of the first aspect of the present invention, wherein when calculating impurity content, impurity A, impurity B, impurity C, impurity
D, the correction factor of impurity E is respectively 0.67,0.76,1.40,1.45,1.26.
According to method of the first aspect of the present invention, wherein the specification of chromatographic column be 250mm × 4.6mm, 5 μm, each impurity phase
It is 0.175 ± 0.015, impurity that for the relative retention time of nicorandil, to be respectively as follows: impurity A, which be 0.117 ± 0.010, impurity B,
It is 0.464 ± 0.045, impurity E is 1.367 ± 0.130 that C, which is 0.258 ± 0.025, impurity D,.
According to method of the first aspect of the present invention, dilution used in various solution wherein is prepared in the preparation of step (3) solution
Liquid is mobile phase A.
According to method of the first aspect of the present invention, dilution used in various solution wherein is prepared in the preparation of step (3) solution
Liquid is mobile phase A and triethylamine with the mixed liquor of the ratio of volume ratio 100:0.11~0.13, e.g. mobile phase A and triethylamine with
The mixed liquor of volume ratio 100:0.12 ratio.
According to method of the first aspect of the present invention, wherein the carboxymethyl in the nicorandil tablet agent comprising 2~15% forms sediment
Powder sodium.
According to method of the first aspect of the present invention, wherein chromatographic column used is the specification of Waters Atlantis T3 brand
For 250 × 4.6mm, 5 μm of chromatographic column.
According to method of the first aspect of the present invention, wherein the carboxymethyl in the nicorandil tablet agent comprising 2~15% forms sediment
Powder sodium, sodium carboxymethyl starch are auxiliary materials most-often used as disintegrating agent in a kind of tablet, are used as disintegration of tablet in pharmaceuticals industry
Its dosage of the sodium carboxymethyl starch of agent usually accounts for the 2~15% of total weight of tablet.The present inventor is in each production to being collected into
It is detected in the nicorandil tablet of manufacturer comprising sodium carboxymethyl starch, and wherein carboxymethyl starch sodium content reaches after measured
2~15% ranges of total weight of tablet.It has been found that test sample is placed in the long period due to the presence of sodium carboxymethyl starch
Impurity A therein, B, C have significant growth afterwards, and can generate a series of secondary impurity, interfere the measurement of impurity C.Furthermore it supplies
Test sample solution is highly unstable, in a very short period of time impurity D will continuous transformation be impurity C, further influence measurement, from this
It is said in a meaning, the present inventor is better for the more excellent nicorandil tablet especially stability of preparation according to these discoveries
Nicorandil tablet provides possibility.In addition, it has had now surprisingly been found that, has been cooperated using chromatographic condition provided by the invention
Specific chromatographic column, for example, Waters Atlantis T3 (250 × 4.6mm, 5 μm), X-select HSS T3 (250 ×
4.6mm, 5 μm), and when preparing various test solution, using being added to about 0.12% (v/v) three second on the basis of mobile phase A
The resulting mixed liquor of amine, which is used as, matches liquid solvent, after combining this three kinds of technical characteristics, the HPLC method that provides can perfectly by
Impurity C is separated with interference impurity, and can be effectively prevented from the reduction of impurity D in test solution, accurately quantifies Buddhist nun gram ground
The impurity that your piece generates avoids that the false height of impurity C is presented and the false low false results of impurity D occurs.
The present inventor in test, by nicorandil is mixed with sodium carboxymethyl starch (tablet A prepared by the present invention,
And compared with not adding the tablet B of sodium carboxymethyl starch), under the conditions of the accelerated test of 40 DEG C of relative humidity 75% place 0,2,
5, related substance is measured by the method for the present invention after 10 days, pay close attention to the variation that each impurity generates and accelerated with the same condition of Nicorandil
Test is compared.It finds in the comparison, compared with tablet B, tablet A is by the mixing with sodium carboxymethyl starch, in sample
Impurity A, B, C are dramatically increased, and there are also the measurements that other low content unknown impuritie peaks generate interference impurity C.Because of carboxymethyl starch
Sodium is auxiliary material most-often used as disintegrating agent in a kind of tablet, and such auxiliary material is contained in product on sale at present in domestic enterprise,
So there is also this phenomenon in commercial samples, cause at present related in the drug standards both at home and abroad and published document
Substance inspection method can not impurity content effectively in quantitative detection country Nicorandil piece, such as see Fig. 2, Fig. 3.In this hair
In the contrasting detection of bright tablet preparation example, this phenomenon is also demonstrated.
Chromatographic condition cooperation of the present invention by creative foundation based on gradient is high to carry resistance to the 100% of carbon amounts and selectivity
The chromatographic column of water phase not only ensure that the available good separation of the polar impurity of nicorandil, but taken into account nicorandil and
The elution of the small impurity of its polarity separates, and the influence that the fluctuation for effectively inhibiting baseline detects impurity.In addition, because supplying
Test sample solution is highly unstable, within 30 minutes time impurity D will continuous transformation be impurity C, face even if taking with existing system
Mode, during ultrasonic dissolution sample, impurity D can also continue to reduce, and impurity C continue to increase, and influence quantifying for impurity.
The unstability for solving solution as a result, has very important realistic meaning.The present inventor by supplement test hair now for
Increase triethylamine 1.2ml in the dilution of test sample solution, the solution especially stability of impurity D can be greatly improved, ensure that
Accuracy in relation to substance-measuring.4 are placed at room temperature or 2~6 DEG C of temperature using the test solution of this diluent preparing
After hour, impurity D is not reduced, and solves the problems, such as that impurity D is unstable.
In the above-mentioned preparation method of the invention the step of, although the specific steps of its description are in certain details or language
In description with the preparation example of following detailed description part described in step different from, however, those skilled in the art
The detailed disclosure of member's full text according to the present invention can summarize approach described above step completely.
Any embodiment in either present invention face can be combined with other embodiments, as long as they are not
It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention
The technical characteristic in scheme is applied, as long as they are not in contradiction.The invention will be further described below.
All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literary
When offering expressed meaning and the inconsistent present invention, it is subject to statement of the invention.In addition, the various terms that use of the present invention and
Phrase has that well known to a person skilled in the art general senses, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explains, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention
Subject to the meaning stated.
Nicorandil, is commonly called as Nicorandil, entitled N- (2- hydroxyethyl) Nicorandil of chemistry, and molecular formula is
C8H9N3O4, it is the first K ~+Channel Opener for clinical ATP sensitivity, clinical research confirmation, it is suitable for all types of
Angina pectoris, including exertional angina pectoris and spasmodic angina, and cardiovascular event occurrence risk can be substantially reduced, improve pre-
Afterwards.
Nicorandil was trial-produceed successfully by Japanese Chugai, oiling drug factory, Mitsubishi in 1978 earliest, was used within 1981
There are international common name Nicorandil in clinical research, nineteen eighty-two, and nineteen eighty-three carries nicorandil medicine yearbook " cardiovascular drugs "
The first volume has completed zoopery, the items research work such as pharmacological toxicity test and clinical test.And reach the practical stage,
It is listed at the beginning of 1984 in Japan.Current market sales of Nicorandil product name includes: Ikorel (in Britain, Australia
With most of Europe area), Dancor (Switzerland), Zynicor (in India), Aprior (Philippine), Sigmart (in Japan,
South Korea and TaiWan, China), glad Horizon (China's Mainland-Xi'an Han Feng) etc..
Nicorandil category nitrate compound is a kind of ATP sensitive Potassium Channel Opener.As nitrate, cigarette
Unrestrained fourth can active cell matter guanylate cyclase, so as to cause intracellular loops guanosine 5-monophosphate increase and intracellular Ca2+ reduction, together
For Shi Yinqi vascular smooth muscle relaxation as a kind of potassium channel openers, Nicorandil increases potassium ion from intracellular outflow, quiet
It ceases film potential negative value to increase, action potential shortens, and the interior stream of calcium is reduced, and intracellular calcium decline causes vascular smooth muscle loose
It relaxes and vasodilation (indirect calcium channel blocking effect), reduces the consumption of ATP.
Myocardial ischemic preconditioning is significant for the severity of reducing myocardial infarction area and mitigation arrhythmia cordis.
There are cardiac muscle and two kinds of ATP sensitive potassium channel of mitochondria recent studies have shown that in cardiac muscle, is pre-processed in regional myocardial ischemia
(IPC) and in cardioprotection what is played a leading role is mitochondrial ATP-sensitive potassium channel.Using selective mitochondrial ATP
Sensitive potassium channel blocking agent 5-HD (5-hydroxydecanote) can block protective effect of the Nicorandil to cardiac muscle cell, and
With concentration dependent.
Nicorandil has as antianginal drug and prevents intracellular calcium free, increases cell membrane to potassium ion
Permeability expands coronary vasodilator, and duration increases coronary blood flow, inhibits the effect of coronarospasm, is preced in expansion
When shape blood vessel, blood pressure, heart rate, myocardial contractive power and myocardial oxygen consumption are had no effect on；Nicorandil also has inhibition blood platelet
Aggregation prevents the effect of thrombosis.The mechanism of action of nicorandil are as follows: be by making coronary vasodilator in vitro under experiment condition
The guanylate enzyme activation of smooth muscle causes the yield of cyclic guanylic acid to increase, so as to cause coronary vasodilation, with other
Nitrite exercising result is similar.In addition, the mechanism of action that coronary blood flow increase and coronary artery spasm inhibit can pass through cell
The hyperpolarization research of film and illustrated.The pharmacological action of nicorandil is mainly as follows
(1) coronary vasodilation acts on: using Lange moral husband (Langendorff) dog as experimental animal, in normal perfusion pressure
Under, thinner coronary artery expansion, and coronary vasodilation thicker when caused ischemic under low perfusion pressure.In addition,
When to the intravenous injection of non-anesthetized dog, thicker expansion coronarius is unrelated with blood flow dependent on dosage.
(2) to the effect of coronary blood flow: 1) being injected intravenously to anesthetized open-chest dog or give Buddhist nun in duodenum can ground
You, the increase of coronary blood flow and lasting and this preparation dosage have dependence.Use revival dog, the heart-lung preparation of dog, Lange
De Fu (Langenforff) dog sample, which is tested, also obtains same result；2) to 6 without arteria coroaria sinistra is narrow and the left heart
Patient's single of room contraction abnormalities gives nicorandil 5mg, implement atrium dextrum pace-making make heart rate increase to 120 beats/min and
It is not carried out under conditions of pace-making, measurement coronary blood flow (continues thermodilution), has under any heart rate out as the result is shown bright
It is aobvious to increase (118-120%).
(3) alleviate coronary artery spasm effect: being tested with the dog that coronary artery segment is narrow, nicorandil can inhibit
The periodically reduction of hat blood flow and the ST of electrocardiogram rises, and gives vinegar methylcholine in the coronary artery of miniature pig or goes first
Coronary artery spasm caused by adrenaline can also be inhibited.
(4) to the effect of cardiac hemodynamic: nicorandil 1) is injected intravenously to anesthetized open-chest dog, the reduction of blood pressure according to
Rely in dosage, but degree is slight, in the case where making the significantly reduced dosage of coronary vascular resistance, do not influence heart rate, myocardial contractive power,
Myocardial oxygen consumption and atrioventricular conduction time；2) 6 are suffered from without the angina pectoris that arteria coroaria sinistra is narrow and left ventricular contraction is abnormal
Person's single is given this product (being equivalent to nicorandil 5mg), and aortic pressure and blood pressure-heart rate product are without significant change.
The pharmacokinetics of nicorandil: oral absorption is fast and complete, bioavilability 75%, 0.5~1 hour blood after medication
Concentration reach to peak value, half-life period (T1/2) are about 1 hour.It is mainly distributed in liver, the heart, kidney, adrenal gland and blood.It passes through in vivo
Nitro is sloughed in hydrolysis, and metabolite pharmacological activity very little is mainly drained from urine.
Metabolism, the excretion of nicorandil: 4 health adult's man's single orals are given with the nicorandil of heavy hydrogen label
20mg investigates metabolism and excretion, the results showed that most of nicorandil can pass through denitrification formation N- (2- hydroxyl second
Base) niacinamide and be metabolized.Occur within 0.5 hour metabolite in blood plasma after giving nicorandil, reaches most highly concentrated after 2 hours
Degree, almost disappears after 8 hours.Excretion rate is respectively as follows: nicorandil 0.7-1.2% in accumulation urine after 24 hours；Metabolin
N- (2- ethoxy) niacinamide 6.8-17.3%.
The Binding rate of serum protein of nicorandil: human serum in vitro test the result shows that, Binding rate of serum protein 34.2-
41.5% (nicorandil concentration is 1-100 μ g/ml).
The indication of nicorandil: it is suitable for coronary heart disease, anginal treatment.For after labour's type, spontaneous type, infarct or
Mixed type angina is effective.To with auricular fibrillation, Heart enlargement angina pectoris, other antianginal drugs need to be used with caution
This product can be selected in patient.
The usage and dosage of nicorandil: oral.5mg one at a time, 3 times a day；Symptom can dose when improving unobvious
Amount: one time 2,3 times a day.
The clinical application situation of nicorandil: coronary heart disease, nicorandil can effectively expand normal coronary artery and narrow coronary artery,
Increase coronary blood flow.And it can be obviously improved prognosis of patients with coronary artery disease, reduce All-cause death.Angina pectoris, nicorandil is due to having
It expands coronary artery, increase coronary blood flow without the pharmacological properties such as load before and after increasing myocardial oxygen consumption, mitigating heart, therefore it is to each
The anginal treatment of type has obvious curative effects.Clinical test proves that once oral nicorandil can extend Patients With Angina Pectoris and move to
Angina pectoris attacks and reduction in ST segment depression are to the time of 1mm, and dosage is positively correlated with the extended time, and curative effect can maintain
6h or so.It can control anginal breaking-out, efficient up to 90% or so.Extend with the course for the treatment of, attack times significantly reduce.Protection
Cardiac muscle cell, nicorandil can reduce Ca2+ influx, and make matrix diastole, volume increase, thus promote at heart for breathing and
Energy generates, simulated ischemia pre-adaptation, protects cardiac muscle cell.Other diseases as caused by microcirculation (such as pulmonary artery
High pressure).
Quality monitoring more efficiently can be carried out to nicorandil tablet by the method for the invention.
Detailed description of the invention
Fig. 1 is the typical HPLC chromatogram that the method for the present invention detects a collection of typical commercially available nicorandil tablet.
Fig. 2, Fig. 3 are detected using the Related substances separation method in the current drug standards both at home and abroad and published document
The chromatogram of impurity content in domestic nicorandil tablet.
Specific embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited
In following embodiments.One of skill in the art, can be with it is understood that under the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention carries out the material and test method arrived used in test general
And/or specific description.Although to realize the present invention many materials and operating method used in purpose be it is known in the art that
But the present invention is still described in this detail as much as possible.
Tablet preparation example: the formula (every amount) of tablet A: nicorandil 5mg, mannitol 85mg, sodium carboxymethyl starch
9mg, magnesium stearate 1mg；Preparation method: being mixed nicorandil, mannitol, sodium carboxymethyl starch and magnesium stearate, dry, tabletting,
To obtain the final product.The formula (every amount) of tablet B: nicorandil 5mg, mannitol 85mg, magnesium stearate 1mg；Preparation method: make nicorandil,
Mannitol and magnesium stearate are mixed, dry, tabletting to get.
Embodiment 1: methodological study of the nicorandil tablet in relation to substance is measured using HPLC corrector factor method
1, method and result
Nicorandil reference substance, impurity A reference substance (National Institute for Food and Drugs Control), impurity B, C, D Working Control
Product (self-control), impurity E working reference substance (Canadian TLC company), nicorandil tablet sample derive from market sampling.
Chromatographic condition uses Atlantis T3C18 chromatographic column, (4.6 × 250mm, 5 μm), with trifluoroacetic acid-triethylamine-
Tetrahydrofuran-water (3:5:3:989) is mobile phase A, with water: tetrahydrofuran: triethylamine: trifluoroacetic acid (972:20:5:3) is stream
Dynamic phase B, according to the form below carry out gradient elution, flow velocity 1.2ml/min, and column temperature is 25 DEG C, Detection wavelength 262nm.
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0.0 | 100 | 0 |
| 22 | 100 | 0 |
| 54 | 0 | 100 |
| 65 | 0 | 100 |
| 66 | 100 | 0 |
| 75 | 100 | 0 |
Take nicorandil tablet fine powder appropriate (being approximately equivalent to nicorandil 20mg), it is accurately weighed, it sets in 10ml measuring bottle, uses
Dilution shaking dissolves and is diluted to scale, shakes up, and filters, takes subsequent filtrate as test solution.Take nicorandil reference substance
20mg, it is accurately weighed, it sets in 10ml measuring bottle, scale is dissolved and be diluted to dilution, is shaken up, precision measures 1ml, sets 100ml
In measuring bottle, with diluted to scale, shake up, as reference substance solution.The present embodiment used diluent is mobile phase A and three
Ethamine is with the mixed liquor of volume ratio 100:0.12 ratio.
Precision measures test solution, each 10 μ l of reference substance solution, is injected separately into liquid chromatograph, records chromatogram, supplies
It is control, impurity peak area with nicorandil peak area in reference substance solution if any known impurities peak in test sample solution chromatogram
It is calculated multiplied by external standard method is pressed after corresponding correction factor.
In test also using be similar to above-mentioned nicorandil tablet and nicorandil reference substance preparation method, prepare impurity A,
Impurity B, impurity C, impurity D, impurity E solution and the system suitability solution comprising these impurity and nicorandil,
To carry out methodology test.
It can be obtained under this chromatographic condition by specificity test, solvent is noiseless to measuring, and nicorandil tablet is through soda acid oxygen
Changing has catabolite peak after high temperature and humidity illumination destroys, but catabolite can not influence to measure with main peak good separation.Respectively
Impurity and principal component are in the 2 μ g/ml concentration ranges of μ g/ml~50, r=1.0000, linear good.Nicorandil detection is limited to
0.6 μ g/ml is quantitatively limited to 2 μ g/ml.Under the reference substance solution concentration of 20 μ g/ml, 6 needle peak area RSD are nicorandil
0.7%, precision is good.Using the chromatographic column of three different lot numbers and the chromatograph of three different brands to nicorandil tablet sample
Product are determined, and have investigated impurity peaks and main peak, and the separating degree between impurity peaks meets the requirements.It is storeed using reference substance
The stock solution of liquid and each impurity is tested with diluted at 7 concentration points in the 2 μ g/ml concentration ranges of μ g/ml~50
Liquid measures under 262nm wavelength, carries out linear regression to peak area with concentration to nicorandil and each impurity respectively, can with Buddhist nun
The correction factor of ground your linear gradient and the ratio calculation impurity of each impurity linear gradient.The correction factor of impurity A, B, C, D, E
Respectively 0.67,0.76,1.40,1.45,1.26.It is measured by sample, three batches of nicorandil tablets of certain same manufacturer's production
Sample impurity mean value is respectively impurity A 0.15%, impurity B 0.13%, impurity C10.60%, impurity D0.87%, impurity
E0.53%, total impurities 13.34%.
2, chromatographic system and wavelength selection
Nicorandil is weakly basic drugs, first attempts to be added without ion-pairing agent, is the buffering liquid near 7 in pH
With the presence of compound state in system, be conducive to its reservation in chromatographic system, through testing, though the ratio for reducing organic phase can
Dramatically increase the separation that retains but be unable to improve nicorandil polar impurity of the nicorandil in chromatographic system.Ion pair is added
Reagent can improve reservation of the polar compound in C18 chromatographic system, final true by groping different mobile phase ratios
It is scheduled on the chromatographic column for cooperating high-carbon carrying capacity under the conditions of trifluoroacetic acid-triethylamine-tetrahydrofuran-water (3:5:3:989) mobile phase,
The available good separation of the polar impurity of nicorandil.Because nicorandil reservation is too strong in the chromatographic system, so
The mode of gradient elution is taken to accelerate the elution of nicorandil and its small impurity of polarity.Impurity is examined to reduce the fluctuation of baseline
The influence out and elution time limitation for taking into account impurity determines chromatographic condition of the present invention through repetition test.Chromatographic condition of the present invention
Middle nicorandil and its most of degradation impurity have absorption maximum at 262nm ± 2nm wavelength, so selected 262nm is side
The Detection wavelength of method.
3, the selection of chromatographic column
In the above-mentioned test of the present embodiment, because watr-proportion is higher in mobile phase, close to 99%, so chromatographic column is preferentially selected
Select the chromatographic column of resistance to 100% water phase of each mainstream vendor.In the method optimization process that the present inventor carries out, successively it is respectively adopted
The chromatographic column of 5 manufacturers totally 8 kinds of resistance to 100% water phases, Waters Atlantis T3 (250 × 4.6mm, 5 μm) is right as the result is shown
The separating effect of impurity is best, at the same only with its with chromatographic column X-select HSS T3 similar in company and filler (250 ×
4.6mm, 5 μm) and Thermo company Syncronis AQ (250 × 4.6mm, 5 μm) chromatographic column have with its similar in separate effect
Fruit selects other brands of test, the chromatographic column of model that can not efficiently separate all impurity, therefore by Waters
Atlantis T3 (250 × 4.6mm, 5 μm) be used as this method chromatographic column proposed model, X-select HSS T3 (250 ×
4.6mm, 5 μm) column and Syncronis AQ (250 × 4.6mm, 5 μm) also still select.
4, the selection of test solution retarder thinner
Since mobile phase A is 100% operation in initial 22min, to make solvent influence minimum, this hair on chromatographic system
Bright people once prepared various test solution as dilution using mobile phase A of course, however unluckily discovery, used
Mobile phase A is that the various test solutions that solvent is prepared are very unstable, and impurity D will continue, greatly within 15 minutes time
It is converted into amount impurity C, influences the measurement of sample.
5, complementary testing
For the present invention in test then, trial increases appropriate triethylamine in preparing dilution used in test solution
(method that other test operations are recorded with the present embodiment 1 its " 1, method and result " part), it was thus unexpectedly found that work as use
The prepared mixed liquor of 0.12ml triethylamine is added in every 100ml mobile phase A as dilution, is surveyed with this diluent preparing HPLC
When the various test solution of examination, the phenomenon that impurity C can be converted into completely to avoid impurity D in the short time in test solution.So
And when triethylamine additive amount is below or above above-mentioned 0.12ml, in presentation test solution impurity is unstable and then shadow
Ring the unacceptable result of detection accuracy；That is, when triethylamine incrementss deficiency is lower than equal to 0.10ml then for examination
Product solution place in 30 minutes time impurity D will continuous transformation be impurity C, excessive be optionally greater than when triethylamine increases
Ammonolysis will be occurred and gradate as impurity B by then placing impurity C in 5 minutes in test solution when 0.14ml；Specific test is such as
Below shown in each complementary testing:
Complementary testing A: above " 1, method and result " referring to the present embodiment 1, tri- second of 0.1ml is added with 100ml mobile phase A
Mixed liquor obtained by amine is prepared the reference substance solution of the 0.1mg/ml of impurity C, D respectively, is then distinguished as the dilution for matching liquid
In 0,0.5,1,2 hour sample introduction, impurity C solution kept stable in 2 hours, but impurity solution D at 0.5 hour
Have and be converted into impurity C on a small quantity, conversion ratio was about 35% at 2 hours, and had been found that the triethylamine amount added in dilution
Lower, then this conversion rate of impurity D to C is faster；
Complementary testing B: above " 1, method and result " referring to the present embodiment 1,0.14ml tri- is added with 100ml mobile phase A
Mixed liquor obtained by ethamine is prepared the reference substance solution of the 0.1mg/ml of impurity C, D respectively, is then divided as the dilution for matching liquid
Not in 0,0.5,1,2 hour sample introduction, then impurity C solution just has about 20% to be converted into impurity B when facing with brand-new, after 1h
Conversion ratio is just completely converted into impurity B just to be up to 80% after 2 hours, impurity solution D kept stable in 2 hours, and
And having been found that the triethylamine amount added in dilution is higher, then this conversion rate of impurity C to B is faster；
Complementary testing C: it when adding 0.11~013ml triethylamine with 100ml mobile phase A, does not find above-mentioned apparent miscellaneous
The conversion of matter D to C or impurity C to B, it is as a result essentially identical with addition 0.12ml triethylamine；
Complementary testing D: it is formed using 100ml mobile phase A addition 0ml, 0.1ml, 0.12ml, 0.14ml, 0.2ml triethylamine
Five kinds of mixed liquors as the dilution for preparing solution, using include nicorandil, it is impurity A, impurity B, impurity C, impurity D, miscellaneous
The mixture that matter E is formed using weight ratio 100:1:1:1:1:1 ratio is tester, it has been found that test solution is placed at room temperature
After 2 hours:
It is kissed using the test result of five kinds of ingredients when mobile phase A/triethylamine=100/0.12 dilution and its theoretical content
It closes,
Buddhist nun is shown using the test result of five kinds of ingredients when mobile phase A/triethylamine=100/0 and 100/0.1 dilution
Can ground that, impurity A, impurity B, the identical still impurity D content as complementary testing A of impurity E and its theoretical content substantially reduce
And impurity C content dramatically increases,
It is shown using the test result of five kinds of ingredients when mobile phase A/triethylamine=100/0.14 and 100/0.2 dilution
Nicorandil, impurity A, impurity D, impurity E and its theoretical content are coincide but the impurity C content as complementary testing B significantly subtracts
Less and impurity B content dramatically increases.
Therefore, in one embodiment of the invention, preparing solution used diluent is every 100ml mobile phase A addition
Mixed liquor obtained by 0.11~013ml triethylamine.
Embodiment 2: the related substance of HPLC corrector factor method measurement nicorandil tablet is used
The related substance in nicorandil tablet is detected using high performance liquid chromatography, operating procedure is as follows:
(1) it is surveyed according to the specification in the contained high performance liquid chromatography of Chinese Pharmacopoeia four general rules 0512 of version in 2015
It is fixed；
(2) chromatographic condition and system suitability: with chromatographic column (this that octadecylsilane chemically bonded silica is filler
Example use WatersAtlantis T3 column, 250 × 4.6mm, 5 μm), with trifluoroacetic acid-triethylamine-tetrahydrofuran-water (3:5:
It is 3:989) mobile phase A, with water: tetrahydrofuran: triethylamine: trifluoroacetic acid (972:20:5:3) is Mobile phase B, shown according to the form below
Gradient elution program carries out gradient elution, flow velocity 1.2ml/min, and column temperature is 25 DEG C, Detection wavelength 262nm,
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0.0 | 100 | 0 |
| 22 | 100 | 0 |
| 54 | 0 | 100 |
| 65 | 0 | 100 |
| 66 | 100 | 0 |
| 75 | 100 | 0 |
In system suitability solution chromatogram, the retention time of nicorandil is (such as 34 within the scope of 33~40min
~38min, special 35~37min), number of theoretical plate should be not less than 5000 based on nicorandil peak, nicorandil and other impurities
Separating degree between peak should be greater than 3；
(3) prepared by solution:
The fine powder for taking the nicorandil tablet for being equivalent to nicorandil 20mg to be ground into, it is accurately weighed, it sets in 10ml measuring bottle, uses
Dilution (taking 100ml mobile phase A that 0.12ml triethylamine is added to be uniformly mixed) shaking dissolves and is diluted to scale, shakes up, and filters, takes
Test solution of the subsequent filtrate as Related substances separation (its concentration is equivalent to 2000 μ g/ml)；
Nicorandil reference substance 20mg is taken, it is accurately weighed, it sets in 10ml measuring bottle, is dissolved with above-mentioned dilution and be diluted to quarter
Degree, shakes up, the reference substance stock solution that concentration is equivalent to 2000 μ g/ml is made；Precision measures reference substance stock solution 1ml, sets 100ml
It in measuring bottle, with diluted to scale, shakes up, as reference substance solution (its concentration is equivalent to 20 μ g/ml)；
Dirt solution: precision weighs each impurity (impurity A, B, C, D, E) 10mg, is set in 10ml measuring bottle respectively, with above-mentioned dilute
It releases liquid and dissolves and be diluted to scale, shake up, the stock solution that each impurity concentration is equivalent to 1000 μ g/ml is respectively prepared；It is accurate respectively
Each impurity stock solution 1ml is measured, is set in 100ml measuring bottle, with diluted to scale, is shaken up, (its is dense as each dirt solution
Degree is equivalent to 10 μ g/ml)；
System suitability solution: taking nicorandil reference substance 20mg, accurately weighed, sets in 10ml measuring bottle, in addition to
Accurate each impurity stock solution 0.1ml of addition is shaken up with diluted to scale respectively in the measuring bottle, as system suitability
Testing liquid (its concentration is equivalent to 2000 μ g/ml of nicorandil, 10 μ g/ml of each impurity)；
(4) it measures:
Precision measures 10 μ l of reference substance solution, injects liquid chromatograph, records chromatogram, reads nicorandil in chromatogram
Retention time, peak area；
Precision measures each 10 μ l of dirt solution, is injected separately into liquid chromatograph, records chromatogram, reads each in chromatogram
The retention time of a impurity, peak area, and determine the retention time of each impurity；
Precision measures 10 μ l of system suitability solution, injects liquid chromatograph, records chromatogram, reads in chromatogram
The retention time of each chromatographic peak, peak area calculate between the number of theoretical plate, nicorandil and other impurities peak at nicorandil peak
Separating degree, calculate each impurity phase for the relative retention time of nicorandil；
Precision measures 10 μ l of test solution, injects liquid chromatograph, records chromatogram, reads nicorandil in chromatogram
And the area of each impurity；If any known impurities peak in test solution chromatogram, with nicorandil peak area in reference substance solution
For control, the content of the impurity in tablets is calculated by external standard method multiplied by after its correction factor with the impurity peak area.
The present embodiment measurement result is as follows:
In system suitability solution chromatogram, the retention time of nicorandil is about 36.0min, because of flow velocity, column
The factors such as temperature fluctuate the influence that ± 0.5min may be caused to retention time；Number of theoretical plate is greater than based on nicorandil peak
5000, the separating degree between nicorandil and other impurities peak is greater than 3, and the mutual separating degree in each other impurities peak is all larger than
1.5；
Using the stock solution of reference substance stock solution and each impurity, with diluted at dense in 2 μ of μ g/ml~50 g/ml
Spend range in 7 concentration point test fluids, measured under 262nm wavelength, respectively to nicorandil and each impurity with concentration to peak
Area carries out linear regression, with the correction factor of nicorandil linear gradient and the ratio calculation impurity of each impurity linear gradient.
Impurity A, B, C, D, E correction factor be respectively 0.67,0.76,1.40,1.45,1.26；
It is measured using the above method of the present embodiment, each impurity phase is respectively as follows: the relative retention time of nicorandil
Impurity A be 0.117 ± 0.010, impurity B be 0.175 ± 0.015, impurity C be 0.258 ± 0.025, impurity D be 0.464 ±
0.045, impurity E is 1.367 ± 0.130；
It can be obtained under the present embodiment chromatographic condition by specificity test, solvent is noiseless to measuring, nicorandil tablet warp
Soda acid oxidation high temperature and humidity illumination has catabolite peak after destroying, but catabolite can not be influenced with main peak good separation
Measurement；
Each impurity and principal component are in the 2 μ g/ml concentration ranges of μ g/ml~50, r=1.0000, linear good；
Nicorandil detection is limited to 0.6 μ g/ml, is quantitatively limited to 2 μ g/ml；
Nicorandil is under the reference substance solution concentration of 20 μ g/ml, and 6 needle peak area RSD are 0.6%, and precision is good.
Using the method for the present embodiment 2, to the totally 18 batch nicorandil tablet sample of 2 manufacturers from Market Extraction
(8~10 batches, each manufacturer), after measured, whole batch sample Impurity A contents of A manufacturer are in 0.1~0.4% range, impurity B
Content in 0.1~0.3% range, impurity C content in 5.6~17.2% ranges, impurity D content is in 0.3~1.0% range
Interior, impurity E content is in 0.4~0.7% range；Whole batch sample Impurity A contents of B manufacturer are in 0.0~0.1% range
Interior, impurity B content in 0.0~0.1% range, impurity C content in 0.3~1.8% range, impurity D content 0.3~
In 0.5% range, impurity E content is in 0.3~0.4% range.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case where without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended power
Benefit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent elements of the claims
Variation is included within the present invention.
Claims (10)
1. the method detected using high performance liquid chromatography to the related substance in nicorandil tablet comprising following behaviour
Make:
(1) it is measured according to the specification in the contained high performance liquid chromatography of Chinese Pharmacopoeia four general rules 0512 of version in 2015；
(2) chromatographic condition and system suitability: with chromatographic column that octadecylsilane chemically bonded silica is filler (for example,
The specification of chromatographic column be 150~300mm (such as 250mm) × 4.6mm, 5 μm), with trifluoroacetic acid-triethylamine-tetrahydrofuran-water
(3:5:3:989) is mobile phase A, with water: tetrahydrofuran: triethylamine: trifluoroacetic acid (972:20:5:3) is Mobile phase B, is pressed
Gradient elution program shown in table carries out gradient elution, flow velocity 1.2ml/min, and column temperature is 25 DEG C, Detection wavelength 262nm,
In system suitability solution chromatogram, the retention time of nicorandil within the scope of 33~40min (such as 34~
38min), number of theoretical plate should be not less than 5000 based on nicorandil peak, and the separating degree between nicorandil and other impurities peak is answered
Greater than 3；
(3) prepared by solution:
The fine powder for taking the nicorandil tablet for being equivalent to nicorandil 20mg to be ground into, it is accurately weighed, it sets in 10ml measuring bottle, with dilution
Liquid shaking, which is dissolved, is simultaneously diluted to scale, shakes up, filters, taking subsequent filtrate as the test solution of Related substances separation, (its is dense
Degree is equivalent to 2000 μ g/ml)；
Nicorandil reference substance 20mg is taken, it is accurately weighed, it sets in 10ml measuring bottle, scale is dissolved and be diluted to above-mentioned dilution,
It shakes up, the reference substance stock solution that concentration is equivalent to 2000 μ g/ml is made；Precision measures reference substance stock solution 1ml, sets 100ml amount
In bottle, with above-mentioned diluted to scale, shake up, as reference substance solution (its concentration is equivalent to 20 μ g/ml)；
Dirt solution: precision weighs each impurity 10mg, is set in 10ml measuring bottle respectively, is dissolved with above-mentioned dilution and is diluted to quarter
Degree, shakes up, the stock solution that each impurity concentration is equivalent to 1000 μ g/ml is respectively prepared；It is accurate respectively to measure each impurity stock solution
1ml is set in 100ml measuring bottle, with diluted to scale, is shaken up, and as each dirt solution, (its concentration is equivalent to 10 μ g/
ml)；
System suitability solution: taking nicorandil reference substance 20mg, accurately weighed, sets in 10ml measuring bottle, in addition to the amount
Accurate each impurity stock solution 0.1ml of addition is shaken up with diluted to scale respectively in bottle, as system suitability
Solution (its concentration is equivalent to 2000 μ g/ml of nicorandil, 10 μ g/ml of each impurity)；
(4) it measures:
Precision measures 10 μ l of reference substance solution, injects liquid chromatograph, records chromatogram, reads the guarantor of nicorandil in chromatogram
Stay time, peak area；
Precision measures each 10 μ l of dirt solution, is injected separately into liquid chromatograph, records chromatogram, reads each miscellaneous in chromatogram
The retention time of matter, peak area, and determine the retention time of each impurity；
Precision measures 10 μ l of system suitability solution, injects liquid chromatograph, records chromatogram, reads each in chromatogram
The retention time of chromatographic peak, peak area calculate point between the number of theoretical plate, nicorandil and other impurities peak at nicorandil peak
From degree, each impurity phase is calculated for the relative retention time of nicorandil；
Precision measures 10 μ l of test solution, injects liquid chromatograph, records chromatogram, reads in chromatogram nicorandil and each
The area of impurity；It is pair with nicorandil peak area in reference substance solution if any known impurities peak in test solution chromatogram
According to calculating the content of the impurity in tablets by external standard method multiplied by after its correction factor with the impurity peak area.
2. the method according to claim 1, wherein the impurity is selected from following impurity A, impurity B, impurity C, impurity D, impurity E:
3. the method according to claim 1, wherein further including the process for measuring and calculating the correction factor of each impurity.
4. according to the method in claim 3, the process is: using the stock solution of reference substance stock solution and each impurity, use is dilute
7 concentration point test fluids that liquid is diluted in the 2 μ g/ml concentration ranges of μ g/ml~50 are released, are measured under 262nm wavelength, respectively
Linear regression is carried out to peak area with concentration to nicorandil and each impurity, it is linearly oblique with nicorandil linear gradient and each impurity
The correction factor of the ratio calculation impurity of rate.
5. the method according to claim 1, wherein when calculating impurity content, impurity A, impurity B, impurity C, impurity D, impurity E
Correction factor be respectively 0.67,0.76,1.40,1.45,1.26.
6. the method according to claim 1, wherein the specification of chromatographic column is 250mm × 4.6mm, and 5 μm, each impurity phase can for Buddhist nun
To retention time, to be respectively as follows: impurity A be 0.117 ± 0.010, impurity B to your phase 5 of ground is that 0.175 ± 0.015, impurity C is
0.258 ± 0.025, it is 1.367 ± 0.130 that impurity D, which is 0.464 ± 0.045, impurity E,.
7. the method according to claim 1, wherein in the preparation of step (3) solution, preparing dilution used in various solution is stream
Dynamic phase A.
8. the method according to claim 1, wherein in the preparation of step (3) solution, preparing dilution used in various solution is stream
Dynamic phase A and triethylamine are with the mixed liquor of the ratio of volume ratio 100:0.11~0.13, and e.g. mobile phase A and triethylamine is with volume ratio
100:0.12 the mixed liquor of ratio.
9. the method according to claim 1, wherein including 2~15% sodium carboxymethyl starch in the nicorandil tablet agent.
10. the method according to claim 1, wherein the specification that chromatographic column used is Waters Atlantis T3 brand is 250
× 4.6mm, 5 μm of chromatographic column.
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| CN115317456A (en) * | 2022-08-17 | 2022-11-11 | 北京科源创欣科技有限公司 | Nicorandil tablet composition and preparation method thereof |
| CN116359394A (en) * | 2023-04-21 | 2023-06-30 | 本溪匠成医药科技有限公司 | High performance liquid chromatography for separating and detecting related substances in nicorandil tablets |
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| CN115317456A (en) * | 2022-08-17 | 2022-11-11 | 北京科源创欣科技有限公司 | Nicorandil tablet composition and preparation method thereof |
| CN116359394A (en) * | 2023-04-21 | 2023-06-30 | 本溪匠成医药科技有限公司 | High performance liquid chromatography for separating and detecting related substances in nicorandil tablets |
| CN116359394B (en) * | 2023-04-21 | 2023-11-17 | 本溪匠成医药科技有限公司 | High performance liquid chromatography for separating and detecting related substances in nicorandil tablets |
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